Human cancers

Over the last three decades, knowledge on the molecular biology of human cancers has vastly expanded. A host of genes and proteins involved in cancer development and progression have been defined and many mechanisms at the molecular, cellular and even tissue level have been, at least partly, elucidated. Insights have also been gained into the molecular mechanisms underlying carcinogenesis by chemical, physical, and biological agents and into inherited susceptibility to cancer. Accordingly, Part I of the book presents many of the molecules and mechanisms generally important in human cancers.

Over the past 20 years, technological advances in molecular biology have
proven invaluable to the understanding of the pathogenesis of human cancer.
The application of molecular technology to the study of cancer has not only
led to advances in tumor diagnosis, but has also provided markers for the
assessment of prognosis and disease progression. The aim of Molecular Analysis
of Cancer is to provide a comprehensive collection of the most up-to-date
techniques for the detection of molecular changes in human cancer.

Telomeres play an important role in cellular aging and cancer. Human
telomeric DNA and RNA G-rich sequences are capable of forming a four-stranded structure, known as the G-quadruplex. Such a structure might be
important for telomere biology and a good target for drug design.

Cell culture is practiced extensively throughout the world today. The techniques
required to allow cells to grow and be maintained outside the body have been developed
throughout the 20th century. In the 50 years since the publication of the first
human cancer cell line, HeLa (1), thousands of cell lines representing most of the
spectrum of human cancer have been derived. These have provided tools to study in
depth the biochemistry and molecular biology associated with individual cancer types
and have helped enormously in our understanding of normal as well as cancer cell
physiology.

Oncogenes in Human Cancer Oncogenes of the kind found in human cancers were initially discovered through their presence in the genome of retroviruses capable of causing cancers in chickens, mice, and rats. The cellular homologues of these viral genes are often targets of mutation or aberrant regulation in human cancer. Whereas many oncogenes were discovered because of their presence in retroviruses, other oncogenes, particularly those involved in translocations characteristic of particular leukemias and lymphomas, were isolated through genomic approaches.

Antiangiogenic Therapy Understanding the molecular mechanisms that regulate tumor angiogenesis may provide unique opportunities for cancer treatment. Acquired drug resistance of tumor cells due to their high intrinsic mutation rate is a major cause of treatment failure in human cancers. ECs comprising the tumor vasculature are genetically stable and do not share genetic changes with tumor cells; the EC apoptosis pathways are therefore intact.

The potential value of artificial neural networks (ANNs) as a predictor of malignancy has
now been widely recognised. The concept of ANNs dates back to the early part of the 20th
century; however, their latest resurrection started in earnest in the 1980s when they were
applied to many problems in the areas of pattern recognition, control, and optimisation.

There have been a significant number of advances
in the field of cancer research since the
first edition of Cancer Biology, which was published
in 1981. These include advances in defining
the genetic and phenotypic changes in cancer
cells, the genetic susceptibility to cancer, molecular
imaging to detect smaller and smaller tumors,
the regulation of gene expression, and the
‘‘-omics’’ techniquesofgenomics, proteomics,and
metabolomics, among others.

Oncogenic viruses are the known etiologic agents in 15% – 20% of all human cancers.
Their impact on global health is signifi cant. The fi rst recognition that cancer can be
caused by a virus dates back to observations of Rous sarcoma virus in chickens almost
100 years ago. However, it was not until the 1970s that the mechanistic basis for
retroviral transformation became clearer. That era was marked by the discovery of
many viral oncogenes and counterpart cellular proto - oncogenes.

Cancer Cell Biology The treatment of most human cancers with conventional cytoreductive agents has been unsuccessful due to the Gompertzian-like growth kinetics of solid tumors (i.e., tumor growth is exponential in small tumors, with increasing doubling times as tumors expand; since conventional chemotherapeutic agents target proliferating cells, noncycling cells in large tumors are relatively resistant). Genetic instability is inherent in most cancer cells and predisposes to the development of intrinsic and acquired drug resistance. Thus, although tumors arise from a single cell (i.e.

PI3K is a heterodimeric lipid kinase that catalyses the conversion of phosphatidylinositol bisphosphate (PIP2) to phosphatidylinositol trisphosphate (PIP3), which acts as a plasma membrane docking site for proteins that contain a pleckstrin homology (PH) domain. These include the serine/threonine kinases Akt and PDK1 that are key downstream effectors of PI3K action (Fig. 80-2). The PI3K pathway is activated in 30–40% of human cancers and is thought to play a critical role in tumor cell survival, proliferation, growth, and glucose utilization.

Signaling Pathways Downstream of Rtks: Ras and PI3K Several oncogene and tumor-suppressor gene products are components of signal transduction pathways that emanate from RTK activation (Fig. 80-2). The most extensively studied are the Ras/mitogen-activated protein (MAP) kinase pathway and the phosphatidylinositol-3-kinase (PI3K) pathway, both of which regulate multiple processes in cancer cells, including cell cycle progression, resistance to apoptotic signals, angiogenesis, and cell motility.

Colon cancer is one of the most common human cancers worldwide. Owing
to its aggressiveness and lethality, it is necessary to determine the mecha-nisms regulating the carcinogenesis of colon cancer. EphrinA5 has been reported to act as a putative tumor suppressor in glioma; however, little is
known concerning the role of this protein in the context of colon cancer.

Mammalian intracellular ribonuclease L (RNase L) is a latent endoribo-nuclease that functions against viral infections as an apoptosis-inducing
protein, and its activity requires intracellular 5¢-end-triphosphorylated-2¢,5¢
oligoadenylates (2-5A) as an activator. Previously, we showed that
RNase L can be activated in human cancer cell line HT1080 by an RNA
polymerase I inhibitor, 1-(3-C-ethynyl-b-d-ribo-pentofuranosyl)cytosine
(3¢-ethynylcytidine; ECyd).

GToligomers, showingadose-dependent cytotoxic effect on
a variety of human cancer cell lines, but not on normal
human lymphocytes, recognize and form complexes with
nuclear proteins.By working with human T-lymphoblastic
CCRF-CEM cells and by using MS and SouthWestern
blotting, we identified eukaryotic elongation factor 1 alpha
(eEF1A) as the main nuclear protein that specifically
recognizes these oligonucleotides.Western blotting and
supershift assays confirmed the nature of this protein and
its involvement in forming a cytotoxicity-related complex
(CRC)....

According to the National Cancer Institute, cancer continues to take
a devastating toll. Among women in the United States, cancer is the
second-leading cause of death after heart disease. Medical researchers
fighting against cancer have made significant progress, however. In
recent years, cancer incidence rates have been stable, and—although
the annual rate of decline in cancer death rates among men have been
twice as large as the declines in women—mortality has decreased for
ten of the top 15 cancers in women.